Characterisation of T cells and antibody responses to Malaria, cross - sectional survey comparing two areas

Lead Research Organisation: MRC Unit, The Gambia

Abstract

Malaria is one of the most common diseases in African children, and a major health problem in The Gambia. Though most cases of malaria are usually mild, severe cases of malaria do also occur, killing approximately one million people each year worldwide. It is thought that clearing the parasite from the body requires a potent effective immune response early during infection. However, an excessive or prolonged immune response can lead to disease. It is therefore important to balance the control of the infection and the control of the immune system. We would like to study cells that regulate immune responses and see whether they are important to control malaria infection. Why some people are able to fight malaria strongly while others get severe malaria is unclear. We know that the ability of the immune system to fight pathogens such as malaria is different in each person. People who have had malaria many times when they are young, or live in an area where many people get malaria rarely get sick. People who live in an area where not many people get malaria are more likely to become more seriously ill. We hope that by comparing people with different levels of exposure to malaria, we can get a better understanding of these immunological differences. We would also like to see if there are differences in the immune system after the rainy season, when there is a lot of malaria around, compared to in the dry season, where there is very little malaria. This may allow us to find new treatments or a vaccine that can prevent severe forms of malaria in the future.

Technical Summary

The important contribution of cell mediated inflammatory responses to control parasite replication in human P. falciparum malaria, and the paramount importance of IFN? in this response, is well established. Equally, sustained and/or excessive inflammatory responses have been conclusively linked to severe pathology in animal malaria models and in human disease. This has led to the hypothesis that the ability to down-regulate inflammatory responses once parasitaemia is under control is crucial to avoid immune mediated pathology and may therefore be an important feature of clinical immunity. Regulatory T cells have been shown to downregulate the immune response in several different models of human disease. Observations made in murine models indicate that these cells may also play a role in malaria infection. In humans, data derived from sporozoite challenged volunteers demonstrate that Foxp3 expressing CD4+CD25+ regulatory T cells can be induced and activated as early as 10 days upon infection with P. falciparum in a proportion of subjects. These cells were shown to down-regulate pro-inflammatory responses and to facilitate parasite growth in vivo. However, it is unknown if natural exposure to malaria activates/induces T regulatory cells. The aim of this study is the phenotypic and quantitative characterisation of Tregs in healthy malaria exposed donors. We therefore propose to perform a descriptive immunological study to characterise the frequency and phenotype of these cells in Gambians of different age with distinct levels of malaria exposure in both the dry season and the rainy season. To maximise differences in malaria exposure, volunteers will be recruited from two different sites: an urban area (Bakau) where data from older surveys suggest there is little malaria transmission, and a rural site, close to the river Gambia (Brefet) where we expect malaria transmission to be higher. Volunteers will be screened for parasites as well as serological responsiveness to MSP119 and Plasmodium falciparum schizont extract (PfSE), in order to assess both cumulative and recent exposure to the parasite, and will be selected accordingly i.e. we will attempt to recruit seronegative donors in Bakau and highly seropositive donors in Brefet. Suitable donors will be recruited from three narrow age bands (children, adolescents, and adults) to determine the phenotype, absolute numbers, and cytokine production of regulatory T cells using flow cytometry and RT-PCR. Lymphocyte counts, sickle cell status and intestinal worm infections will be taken into account for analysis. Donors will be followed between surveys by means of a questionnaire every two weeks to detect clinical malaria cases during the time of the study. I will assess the number of Tregs ex-vivo, as well as after culture with malarial antigens. I will also assess cytokine production of T cells after culture. As cells could differ in their efficiency rather than in numbers, we would like to measure their function by using a proliferation assay. I will assess their response to parasitized erythrocytes, as well as other pathogen derived antigens such as PPD to assess the specificity of the response.

Publications

10 25 50
 
Description village meetings 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact Presentation of the data, call for improvements in recruitement process, thanksgiving meal

Improved relationship with participants
Year(s) Of Engagement Activity 2007,2008